This application is a 371 application of PTC/EP98/05558, filed Sep. 3, 1998.
This invention relates to pyrazolo[1,5-b]pyridazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.
The invention thus provides the compounds of formula (I) 
and pharmaceutically acceptable derivatives thereof in which:
R0 is halogen, C1-6alkyl, C1-6alkoxy, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5;
R1 and R2 are independently selected from H, C1-6alkyl, C1-6alkyl substituted by one or more fluorine atoms, C1-6alkoxy, C1-6hydroxyalkyl, SC1-6alkyl, C(O)H, C(O)C1-6alkyl, C1-6alkylsulphonyl, C1-6alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)nNR4R5, (CH2)nSC1-6alkyl or C(O)NR4R5; with the proviso that when R0 is at the 4-position and is halogen, at least one of R1 and R2 is C1-6alkylsulphonyl, C1-6alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)nNR4R5 or (CH2)nSC1-6alkyl, C(O)NR4R5;
R3 is C1-6alkyl or NH2;
R4 and R5 are independently selected from H, or C1-6alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring; and
n is 1-4.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
The term halogen is used to represent fluorine, chlorine, bromine or iodine. The term xe2x80x98alkylxe2x80x99 as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.
Preferably, R0 is at the 3- or 4-position of the phenyl ring, as defined in formula (I).
Preferably, R1 is at the 6-position of the pyridazine ring, as defined in formula (I).
Preferably, R0 is F, C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)1-3NR4R5. More preferably R0 is F, C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms.
Preferably, R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms, O(CH2)1-3CO2C1-4alkyl, O(CH2)1-3SC1-4alkyl, (CH2)1-3NR4R5, (CH2)1-3SC1-4alkyl or C(O)NR4R5 or, when R0 is C1-6alkyl, C1-6alkoxy, O(CH2)nNR4R5, may also be H. More preferably R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms or, when R0 is C1-6alkyl, C1-6alkoxy, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5, may also be H.
Preferably, R2 is H.
Preferably, R3 is methyl or NH2.
Preferably R4 and R5 are independently C1-3alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring.
Preferably, n is 1-3, more preferably 1 or 2.
Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R0 is F, C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5; R1 is C1-6alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-4alkyl, O(CH2)nSC1-4alkyl, (CH2)nNR4R5, (CH2)nSC1-4alkyl or C(O)NR4R5 or, when R0 is C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR4R5, may also be H; R2 is H; R3 is methyl or NH2; R4 and R5 are independently C1-3alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring; and n is 1-3.
Within group A, there is provided another group of compounds (group A1) wherein R0 is F, methyl, C1-2alkoxy, OCHF2; or O(CH2)nNR4R5; R1 is methylsulphonyl, OCHF2, O(CH2)nCO2C1-4alkyl, O(CH2)nSCH3, (CH2)nNR4R5, (CH2)nSCH3 or C(O)NR4R5 or, when R0 is methyl, C1-2alkoxy, OCHF2, or O(CH2)nN(CH3)2, may also be H; R2 is H; R3 is methyl or NH2; R4 and R5 are both methyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring; and n is 1-2.
Within group A, there is provided a further group of compounds (group A2) wherein R0 is F, C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms; R1 is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms or, when R0 C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms, may also be H; R2 is H; and R3 is methyl or NH2.
Within groups A, A1 and A2, R0 is preferably at the 3- or 4-position of the phenyl ring and R2 is preferably at the 6-position of the pyridazine ring.
It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
Particularly preferred compounds of the invention are:
3-(4-methanesulfonyl-phenyl)-2-(4-methoxy-phenyl)-pyrazolo[1,5-b]pyridazine;
6-difluoromethoxy-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
2-(4-fluoro-phenyl)-6-methanesulfonyl-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
2-(4-difluoromethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
4-[2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazin-3-yl]-benzenesulfonamide;
6-difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine;
and pharmaceutically acceptable derivatives thereof.
Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.
In view of their selective COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of the pain (both chronic and acute), fever and inflammation of a variety of conditions and diseases. Such conditions and diseases are well known in the art and include rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold; lower back and neck pain; headache; toothache; sprains and strains; myositis; neuralgia; synovitis; arthritis, including rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.
The compounds of the invention may also be useful for the treatment of other conditions mediated by selective inhibition of COX-2.
For example, the compounds of the invention may inhibit cellular and neoplastic transformation and metastatic tumour growth and hence be useful in the treatment of certain cancerous diseases, such as colonic cancer.
Compounds of the invention may also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore may be of use in the treatment of stroke; epilepsy; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).
Compounds of the invention also inhibit prostanoid-induced smooth muscle contraction and hence may be of use in the treatment of dysmenorrhoea and premature labour.
Compounds of the invention inhibit inflammatory processes and therefore may be of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Chron""s disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin""s disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet""s syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.
Compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.
Compounds of the invention may also be useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Atzheimer""s disease, Pick""s disease, Huntington""s chorea, Parkinson""s disease and Creutzfeldt-Jakob disease), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space occupying lesions, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by selective inhibition of COX-2.
According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from a condition which is mediated by selective inhibition of COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative.
According to another aspect of the invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by selective inhibition of COX-2, such as an inflammatory disorder.
According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include pain relievers such as a glycine antagonist, a sodium channel inhibitor (e.g. lamotrigine), a substance P antagonist (e.g. an NK1 antagonist), acetaminophen or phenacetin; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (e.g. an iNOS or an nNOS inhibitor); an inhibitor of the release, or action, of tumour necrosis factor xcex1; an antibody therapy (e.g. a monoclonal antibody therapy); a stimulant, including caffeine; an H2-antagonist, such as ranitidine; a proton pump inhibitor, such as omeprazole; an antacid, such as aluminium or magnesium hydroxide; an anfiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive, such as codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan; a diuretic; or a sedating or non-sedating antihistamine. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.
The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
The compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. The pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets (including sub-lingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
For transdermal administration, the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle.
The compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
As stated above, the compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
A proposed daily dosage of a compound of formula (I) for the treatment of man is 0.01 mg/kg to 500 mg/kg, such as 0.05 mg/kg to 100 mg/kg, e.g. 0.1 mg/kg to 50 mg/kg, which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0.25 mg/kg to 10 mg/kg may be suitable for systemic administration.
Compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure.
Suitable methods for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof are described below. In the formulae that follow R0 to R5 and n are as defined in formula (I) above unless otherwise stated; HaI is a halogen, such as Br or I; Xxe2x88x92 is a counterion, such as Ixe2x88x92; and alkyl is as previously defined.
Thus according to a first process (A), compounds of formula (I) may be prepared by reacting a compound of formula (II) 
or a protected derivative thereof with a boronic acid of formula (III) 
or a suitable derivative thereof in the presence of a suitable transition metal catalyst. Suitable derivatives of formula (III) include boronic acid esters, such as those described in R. Miyaura et al, J. Org. Chem., 1995, 60, 7508-7510. Conveniently, the reaction is carried out in a solvent, such as an ether (e.g. 1,2 dimethoxyethane); in the presence of a base, such as an inorganic base (e.g. sodium carbonate); and employing a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0).
According to a another process (B), compounds of formula (I) wherein R3 is C1-6alkyl may be prepared by oxidising a compound of formula (IV) 
or a protected derivative thereof under conventional conditions. Conveniently the oxidation is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as Oxone(trademark)) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between xe2x88x9278xc2x0 C. and ambient temperature.
According to a another process (C), compounds of formula (I) wherein R1 is C1-6alkylsulphonyl may be prepared by oxidising a compound of formula (V) 
or a protected derivative thereof under conventional conditions. Conveniently the oxidation is effected in the manner described just above for process (B).
According to a another process (D), compounds of formula (I) wherein R1 is C1-6alkoxy substituted by one or more fluorine atoms may be prepared by reacting an alcohol of formula (VI) 
or a protected derivative thereof with a halofluoroalkane under conventional conditions. Conveniently the reaction is effected in a solvent, such as a polar solvent (e.g. N,N-dimethylformamide), in the presence of a strong base, such as an inorganic hydride (e.g. sodium hydride), at about ambient temperature and using the appropriate bromofluoroalkane to give the desired compound of formula (I).
According to another process (E) compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors. The following procedures are illustrative of suitable interconversions.
Compounds of formula (I) wherein R1 or R2 represent C1-6alkyl substituted by one or more fluorine atoms may be prepared from the appropriate compound of formula (I) wherein R1 or R2 is C1-6hydroxyalkyl, C(O)H or C(O)C1-6alkyl, by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for example, diethylaminosulphur trifluoride. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as xe2x88x9278xc2x0 C.
Compounds of formula (I) wherein R1 or R2 represent C(O)H may be prepared from the corresponding compound of formula (I) wherein R1 or R2 represent CH2OH by oxidation. Suitable oxidising agents include, for example, manganese (IV) oxide. Conveniently the oxidation is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. chloroform), and at elevated temperature (e.g. reflux).
Compounds of formula (I) wherein R1 or R2 represent C1-6hydroxyalkyl, and wherein the hydroxy group is attached to the carbon linked to the pyridazine ring, may be prepared by reduction of the compound of formula (I) wherein R1 or R2 represent the corresponding aldehyde or ketone. Suitable reducing agents include hydride reducing agents, such as diisobutylaluminium hydride.
Conveniently the reduction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as xe2x88x9278xc2x0 C.
As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions.
Another process (F) for preparing compounds of formula (I) thus comprises deprotecting protected derivatives of compounds of formula (I).
The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora W. Greene and Peter G. M. Wuts, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups.
Compounds of formula (II) may be prepared by halogenating compounds of formula (VII) 
by conventional means.
Thus esters of formula (VI) are first hydrolysed to their corresponding acids, for example by treatment with a strong base (e.g. sodium hydroxide), in the present of a solvent (e.g. ethanol) and at elevated temperature. The corresponding acid is then treated with a halogenating agent, conveniently at ambient temperature and in a solvent (e.g. chlorinated hydrocarbon), under which conditions the acid undergoes both halogenation and decarboxylation. Conveniently, the halogenating agent is a brominating agent, such as bromine in the presence of a strong acid (e.g. hydrobromic acid in acetic acid) or N-bromosuccinimide, to yield the corresponding compound of formula (II) wherein Hal is bromine.
Esters of formula (VII) may be prepared by reacting a compound of formula (VIII) 
with an aminopyridazinium complex of formula (IX) 
under conventional conditions. Conveniently the reaction is effected in the presence of a base, such as potassium carbonate, a solvent, such as N,N-dimethylformamide and at ambient temperature.
Boronic acids of formula (III) are either known compounds or may be prepared by literature methods such as those described in, for example, EPA publication No.533268.
Compounds of formulae (IV), (V) and (VI) may be prepared by methods analogous to those described for the preparation of the compound of formula (I) from compounds of formula (II).
Compounds of formula (VIII) are either known compounds or may be prepared by literature methods such as those described in, for example, D H Wadsworth et al, J Org Chem, (1987), 52(16), 3662-8 and J. Morris and D. G. Wishka, Synthesis (1994), (1), 43-6.
Compounds of formula (IX) are either known compounds or may be prepared by literature methods such as those described in, for example, Y Kobayashi et al, Chem Pharm Bull, (1971), 19(10), 2106-15; T. Tsuchiya, J. Kurita and K. Takayama, Chem. Pharm. Bull. 28(9) 2676-2681 (1980) and K Novitskii et al, Khim Geterotskil Soedin, 1970 2, 57-62.
Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formula (II) are key intermediates and represent a particular aspect of the present invention.
Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.
Solvates (e.g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.